tbuckley/cabot-search huggingface dataset:
BIOM-32. EVS CARRYING TENASCIN-C ENABLE TUMOR-SPECIFIC MUTATION ANALYSIS IN GLIOBLASTOMA PATIENTS
Authors: Amanda Salviano-Silva, Cecile Maire, Kathrin Wollmann, Rudolph Reimer, Julia Neumann, Matthias Dottermusch, Ulrich Schüller, Jens Gempt, Dieter Henrik Heiland, Manfred Westphal, Katrin Lamszus, Franz L Ricklefs
Journal: Neuro-Oncology (2023)

Abstract Extracellular vesicles (EVs) transport biological and specific information from tumors into the bloodstream, enabling non-invasive detection of tumor material and disease monitoring. Based on a proteomics screen, we performed immunophenotyping of eight glioma-related antigens (tenascin-C (TNC), integrin-beta 1 (ITGB1), profilin-1 (PFN1), CD44, CD133, GPNMB, HLA-II, SPARC) and tetraspanins (CD9, CD63 and CD81) in plasma EVs from GBM patients (before and after surgery (n = 38)), from matched GBM relapse patients (n = 11), and from healthy donors (HD, n = 12) using imaging flow cytometry. Double-positive TNC+/CD9+ EVs showed the strongest differences per mL of plasma in primary (FC = 7.6, p&amp;lt; .0001, ROC analysis AUC = 81%) and relapsed GBM (FC = 16.5, p&amp;lt; .0001; AUC = 90%) compared to HD subjects. High TNC signals were also observed in GBM-EVs by immunogold electron microscopy compared to HD-EVs. In paired analysis, TNC+/CD9+ EVs showed a 3.9-fold decrease after tumor removal (p&amp;lt; .001) and re-increased at GBM recurrence in these patients (FC = 8.4, p&amp;lt; .05; AUC = 84%). In tissue samples, TNC levels were 5.4-fold higher in GBM patients than in non-neoplastic cortex controls (p&amp;lt; .01) measured by immunohistochemistry and correlated positively with plasma TNC+/CD9+ EV levels in RTK-I/II GBM patients (r = 0.42, p&amp;lt; .05). Accordingly, spatial transcriptomics of GBM tissue sections revealed that TNC is specifically overexpressed in GBM cells. Furthermore, magnetic sorting of TNC in plasma EVs allowed detection of GBM-specific TERT*C228T mutations by digital droplet PCR. Mutated TERT DNA was enriched in TNC+ EVs (n = 13) compared to TNC- EVs (FC = 110, p&amp;lt; 0.0001), total EV DNA (FC = 36.7, p&amp;lt; 0.01), and cfDNA (FC = 7.2, p &amp;lt; 0.05). In conclusion, we identified TNC as a biomarker in circulating EVs from GBM patients that can be isolated and used for tumor-specific mutation analysis.
CTNI-57. PRELIMINARY RESULTS OF A PHASE 1 TRIAL OF ORAL GALLIUM MALTOLATE IN RECURRENT GLIOBLASTOMA
Authors: Jennifer Connelly, Casey Zoss, Kathleen Schmainda, Mona Al-Gizawiy, Fernando Santos Pinheiro, Christopher Chitambar
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive brain tumor with a dismal prognosis. New drugs that exploit previously underexplored cancer-related pathways are needed. We and others have shown that GBM stem cells require significantly greater amounts of iron than normal cells to drive critical iron-dependent processes that are altered in malignancy. We showed that oral gallium maltolate (GaM), an iron-targeting metal compound, has significant activity against GBM stem cells in vitro and shrinks GBM tumors and prolongs survival in a rat brain tumor model. GaM’s mechanisms include inhibition of cellular iron homeostasis, ribonucleotide reductase, and mitochondrial complex 1. Further study of GaM’s toxicity and benefit in patients with recurrent GBM is warranted. METHODS The Phase 1 trial design follows a 3 + 3 dose escalation scheme. Eligible patients will receive GaM at 3 dose levels: 500, 1,000, or 1,500 mg/day for a minimum of two 28-day cycles. Hepatic, renal, and hematologic functions, iron panel, and gallium levels are monitored every 2 weeks. Toxicity and tumor response are assessed by NCI CTCAE criteria and by RANO criteria, respectively. Patients with responding or stable disease may continue treatment with monitoring. RESULTS Ten patients have completed treatment at dose levels 1 and 2 and eight patients are evaluable. Four patients enrolled after first recurrence while the other four patients enrolled after their second, third (2 patients) and fourth recurrence. Median progression-free survival (PFS) on treatment was 118 days. Three patients experienced PFS &amp;gt;180 days and two of those patients remain on treatment. To-date, no dose-limiting toxicities (DLTs) at dose levels 1 and 2 have been encountered. CONCLUSIONS Oral GaM is well tolerated without significant DLTs to date. An additional 6 patients are presently enrolled at dose-level 3. Updated toxicity data and clinical outcomes of the study will be presented at the annual SNO meeting.
DDEL-01. UTILIZING SENSOR ARRAYS FOR INTRACRANIAL PRESSURE (ICP) RESPONSE TO CEREBROSPINAL FLUID (CSF) DRUG ADMINISTRATION, AND POTENTIAL IMPLICATIONS FOR PERSONALIZED CARE IN CNS METASTASES PATIENTS
Authors: Nisheka Vanjani, Rajan Patel, Marcie Glicksman, Grace Lee, Priya Kumthekar
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with leptomeningeal carcinomatosis (LC) may have elevated intracranial pressure (ICP) due to LC cancer cells having the potential to obstruct the arachnoid granulations.,Given that LC treatment may involve intrathecal (IT) drug delivery, monitoring ICP may be important for safe IT drug delivery. The EnClear device is a novel CNS drug delivery device with both intracranial and intralumbar CSF access and single-use sensing arrays that measure ICP in these dual locations. METHODS This is a non-human primate (NHP) study on three healthy NHP subjects undergoing IT gene therapy via intracerebroventricular (ICV). The sensor arrays measured ICP before, during, and after ICV infusion in both intracranial and lumbar locations. Our goal was to compare individual subject pressure response to drug administration as well as to compare lumbar and cranial pressure waveforms for concordance. Pressure response was quantified as change in pressure (ΔP) following volume (ΔV) administration, known as intracranial elastance (ΔP/ΔV). RESULTS Significant correlations were observed between ventricular and lumbar ICP waveforms with an average of 0.88 correlation coefficient. Pressure measurements between subjects demonstrated variable response to identical infusion volumes, with maximum pressures ranging from 20 mmHg to 40 mmHg. Intracranial elastance was calculated for each subject during infusions and resulted in a range of 12 to 36 mmHg/mL, a 3-fold difference in elastance between subjects. CONCLUSION In healthy NHPs, changes to cranial volume and pressure response can be measured in the lumbar space with good correlation between the two measurement locations. Despite this consistency between these two locations on the same subject, intersubject variability was seen despite identical drug administration. Pressure waveform sensing systems can be incorporated in the future to enable clinicians to understand individual patient brain compliance and leverage this knowledge for personalized drug delivery, particularly in patients with LC.
DNAR-01. PAR-MEDIATED DNA DAMAGE SIGNALING IN IDH MUTANT GLIOMAS: COMBINING PARG INHIBITION AND RADIATION FOR SELECTIVE CYTOTOXICITY
Authors: Yosuke Kitagawa, Ali Nasser, Chia Chang, Lisa Melamed, Julie Miller, Hiroaki Wakimoto, Daniel Cahill
Journal: Neuro-Oncology (2023)

Abstract Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy have been proven to be effective treatments for IDH mutant gliomas. Poly (ADP-ribose) (PAR) mediates DNA damage response and is regulated by opposing enzymes: poly (ADP-ribose) polymerases (PARPs) synthesize PAR, while poly (ADP-ribose) glycohydrolase (PARG) breaks it down. Combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells leads to imbalanced NAD sequestration into PAR, causing metabolic lethality. This study characterizes the combination of PARGi and radiation. PARGi monotherapy showed no difference between IDH mutant and wild-type cells. However, we found that combining PARGi with radiation significantly increased cytotoxicity in IDH mutant glioma models, similar to PARPi and radiation. (Wang et al, ACi.Adv. 2020) Our findings showed that unlike TMZ+PARGi, PARGi and radiation did not consume and deplete NAD. Cytotoxicity was partially reversed by IDH inhibitor, highlighting the contribution of PAR-mediated DNA damage signaling in IDH mutant contexts. This convergence of vulnerabilities in IDH mutant cells identifies PAR-mediated DNA repair mechanisms that operate independently of NAD metabolism. IDH mutant enzyme generates 2 hydroxyglutarate (2HG), which is critical early in tumor development. However, the effect of 2HG on radiation sensitivity varies across cellular contexts. In this study, we found that IDH1 mutation and 2HG production enhance radiosensitivity in glioma cells both in vivo and in in vitro models, facilitated by PAR-dependent mechanisms. This augmentation of radiosensitivity is associated with S-phase blockage of the cell cycle, unveiling a vulnerability in the replication process of these cancer cells. In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways, augmenting cytotoxicity specifically in IDH mutant gliomas. Targeting PAR during radiation holds promise for treating IDH mutant gliomas, tailoring therapy to maximize durability while minimizing impact on normal cells.
STEM-05. HYPOXIA AND ACIDOSIS PROMOTE YAP/TAZ ACTIVATION, POTENTIALLY SUPPORTING GLIOMA STEM CELL MAINTENANCE IN THE PERI-NECROTIC ZONES
Authors: Ling-Kai Shih, Jiabo Li, Tatiana Carneiro-Lobo, Cheryl Olson, Daniel Brat
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly malignant brain tumor characterized by rapid growth and poor clinical outcomes. The development of necrosis is associated with massive tumor microenvironment (TME) reshaping and rapid progression characterized by accumulation of tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) in peri-necrotic zones. Using Ivy-GAP and single-cell RNA seq data, we found that many canonical stem-cell associated transcription factors (SOX2, OLIG2, FOXM1) were not upregulated in the hypoxic peri-necrotic zone, yet Hippo transcriptional activation was consistently noted under these conditions. We hypothesized that Hippo activation promotes GSC stemness and may be due to direct effects of hypoxic; the acidic conditions associated with necrosis; or by cytokines secreted by adjacent TAMs. Using patient-derived GBM neurosphere cultures, we exposed glioma cells to 1% hypoxia and found that nuclear expression of YAP1 and TAZ, as well as Hippo pathway readout CYR61, were upregulated compared to normoxia (21%) at 48 hrs, indicating Hippo activation. Exposing cells to an acidic environment (pH 6.3) also caused Hippo transcriptional activation independent of hypoxia. Using single-cell RNA-seq data, we uncovered potential hypoxia-regulated upstream genes that could be responsible for nuclear YAP/TAZ transportation under hypoxia, including Zyxin, WBP2, and PP2A. We also found that culturing GBM cells with media conditioned by human primary macrophages activated Hippo transcription. Using human cytokine arrays, we identified cytokines that showed increased levels in TAM-conditioned media, including EGF, CXCL8, TGF-β, and CXCL5. Treating GBM cells with either hypoxia or a pharmacological activator of YAP/TAZ led to the upregulation of proteins in the inhibitor of differentiation (ID) family (ID1, ID2), which could represent a downstream mechanism related to stem-like behavior following Hippo activation. Our data support the conclusion that hypoxia and TAM cytokines directly stimulate YAP/TAZ activation to potentially promote GSC maintenance in the GBM peri-necrotic niche.
EPCO-04. SPATIAL TRANSCRIPTOMIC ANALYSIS OF MALIGNANT PERIPHERAL NERVE SHEATH TUMORS REVEALS THERAPEUTICALLY TARGETABLE MOLECULAR SIGNATURES IN REGIONS UNDERGOING HISTOPATHOLOGIC TRANSFORMATION
Authors: Kanish Mirchia, Soo-Jin Cho, Alyssa T Reddy, Line Jacques, Melike Pekmezci, Arie Perry, David Raleigh, Harish Vasudevan
Journal: Neuro-Oncology (2023)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) evolve from plexiform neurofibromas (pNF) in patients with neurofibromatosis type-1 (NF-1) yet the cellular and transcriptomic mechanisms underlying this transformation remain unclear. Here, we perform spatial gene expression profiling on fifteen MPNSTs to correlate histologic observations with transcriptomic programs and identify mechanisms underlying malignant transformation. METHODS: Fifteen MPNSTs, including tumors with a histopathologically defined transition zone between adjacent low-grade and high-grade areas (n=3), were retrospectively identified. Spatial transcriptomic profiling was performed using Visium followed by downstream processing with SpaceRanger, Seurat, Harmony, and monocle. RESULTS: 50,807 unique spatial transcriptomes were distributed across 17 unique clusters, of which 12 were enriched for tumor cells and 5 for non-tumor microenvironment cells based on histologic evaluation, unsupervised cell-type assignment, marker gene expression, and cell signature gene sets. Transcriptomic clusters in low-grade areas were enriched for genes regulating mononuclear cell migration and cell-cell adhesion, while high-grade regions were enriched for Ras/Raf/MEK/ERK target genes, anti-apoptotic programs, and extracellular matrix reorganization genes. Trajectory inference beginning in low grade regions revealed spatially organized molecular signatures of malignant transformation enriched for cell cycle progression within histopathologically homogeneous regions. Moreover, the intermediate transformation zone between low-grade neurofibromatous and high-grade MPNST histopathologic regions was marked by loss of cell differentiation genes and increased cell cycle progression. CONCLUSIONS: Spatial transcriptomic analysis elucidates the cellular and gene expression patterns underlying progression from pNF to MPNST. Distinct cell populations exist across low-grade, transformation zone, and high-grade regions in MPNSTs highlighted by alterations in Ras/Raf/MEK/ERK signaling, cell differentiation and cell cycle programs, shedding light on targets for combinatorial molecular therapy to decrease the risk of malignant transformation and serving as a biomarker of aggressive peripheral nerve tumors to complement conventional histopathology.
DNAR-02. MICROGLIA IN THE GLIOBLASTOMA MICROENVIRONMENT ASSIST REPAIR OF RADIATION INDUCED DNA DAMAGE IN A CONTACT INDEPENDENT MANNER
Authors: Sravya Palavalasa, Ava Singer, Andrew Scott, Kari Wilder-Romans, Sunita Shankar, Visweswaran Ravikumar, Sagnik Bhadury, Anthony Andren, Peter Sajjakulnukit, Weihua Zhou, Costas A Lyssiotis, Arvind Rao, Wajd Al-holou, Daniel R Wahl
Journal: Neuro-Oncology (2023)

Abstract Rapid repair of DNA damage mediates genotoxic therapy resistance and poor prognosis in glioblastoma (GBM). The GBM tumor microenvironment (TME) is heterogenous, and we hypothesized that non-malignant cells in the GBM TME support the repair of DNA damage in glioblastoma cells. Consistent with this hypothesis, we found that GBM tumors grown intracranially in mice had rapid DNA repair and were resistant to radiation when compared to tumors of identical genotype grown extracranially in mouse flanks. Further interrogation of irradiated intracranial tumors using gamma-H2AX immunofluorescence revealed spatial heterogeneity in DNA damage repair, with spatially separate regions of rapid and slow gamma-H2AX resolution. Paired spatial transcriptomic analysis and gamma-H2AX immunofluorescence revealed that tumor regions with rapid DNA repair were rich in microglia and enriched for inflammatory response and epithelial to mesenchymal transition (EMT) pathway transcripts. Spatial transcriptomic analysis of patient tissue revealed that regions enriched in DNA damage repair pathways are also enriched for microglia and not other non-malignant cell types. Having nominated microglia, we then cocultured GBM cells and microglia and found that GBM cells cocultured with microglia repair DNA damage faster in a contact-independent manner. Hence, we show that microglia in the GBM microenvironment assist GBM cells to repair radiation induced DNA damage through inflammatory response and EMT and hence, mediate treatment resistance.
DISP-02. PATTERNS IN THE INCIDENCE OF BRAIN METASTASIS BY RACE AND ETHNICITY: A SYSTEMATIC REVIEW
Authors: David Gomez, Jeffrey Feng, Holly Dicharry, Stephanie Cheok, Erion Musabelliu, Gabriel Zada
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Despite advancements in cancer treatment, the incidence of brain metastases (BM) continues to rise which necessitates risk factor analyses. Although current literature indicates racial variance in BM incidence, there exists a major knowledge gap in understanding associations between race/ethnicity, BM incidence, and subtypes which emphasizes the need for a systematic review. We aimed to analyze the relationship between BM incidence, race/ethnicity, and primary cancer type. METHODS Using PRISMA guidelines, a systematic review of PubMed and Ovid databases from January 2000 to January 2023 for terms related to BM, ethnicity and race, in conjunction with incidence was conducted. Inclusion criteria comprised peer-reviewed journals with ages &amp;gt; 18, sample size &amp;gt; 100, primary malignancy diagnosis with evidence of BM, and descriptions of patient race or ethnicity. RESULTS Of 806 identified studies, 11 articles primarily utilizing US data were included for final analysis. Lung and bronchus cancers, revealed the highest incidence of BM in Asian patients, followed by Black, White, and American Indian/Alaska Natives (P&amp;lt; .001), despite overall increased incidence of primary cancer in Black patients. Breast cancer revealed highest BM incidence in American Indian/Alaska Natives (5.9%), followed by Black (5.0%), White (3.6%), and Asian/Pacific Islanders (3.5%) (P&amp;lt; .001). When compared to White and Hispanics only, Black patients had greater incidences of BM (OR: 2.26, 95% CI: 1.57–3.25). Lower incidence of BM for esophageal cancer was observed in Black patients compared to White patients (OR=0.38; 95% CI: (0.16–0.89); P= 0.026). No significant differences were observed in BM incidence for bladder, prostate, or non-small cell and small cell lung cancers. CONCLUSIONS Our review suggests that BM incidence does vary amongst racial/ethnic groups dependent on primary cancer type. Differences may be due to numerous factors, underscoring the need for more work with inclusive, diverse cohorts to tackle BM disparities.
CTNI-79. PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE ANTI-NERVE GROWTH FACTOR (NGF) ANTIBODY TANEZUMAB IN SUBJECTS WITH MODERATE TO SEVERE PAIN DUE TO SCHWANNOMATOSIS
Authors: Scott R Plotkin, Jennifer Da, Danielle Silverman, Vanessa Merker, Ina Ly, Alona Muzikansky, Michael Parsons, Pamela Wolters, Lei Xu, Mark Brown, Scot Styren, Mehrdad Haghpassand, Justin T Jordan
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Schwannomatosis (SWN) is a rare neurogenetic condition (prevalence 1:125,000) characterized by multiple schwannomas and severe chronic pain. Increased expression of nerve growth factor (NGF) has been identified in painful schwannomas. METHODS We conducted a single-institution, phase 2, randomized, double-blind, placebo-controlled trial of tanezumab, an anti-NGF antibody. Eligibility criteria included age ≥ 18; moderate-to-severe SWN-related pain; ability to discontinue NSAIDs; and absence of osteoarthritis. Participants were treated with tanezumab 10 mg SQ or placebo (double-blind treatment) followed by tanezumab 10 mg SQ (single-arm treatment). The primary endpoint was change in NRS-11 scores between days 1 and 57 (double-blind). Secondary endpoints included change in PROMIS-Pain Interference (PI) T-scores. RESULTS Nine subjects were enrolled (median age 44 years, 7 females). At baseline, mean NRS-11 score was 7.6 (SD 2.1) and mean PROMIS-PI T-score was 63.2 (SD 6.6). During double-blind treatment, four participants were randomized to receive tanezumab (early group) and five were randomized to placebo (delayed group). For the early group, the mean change in NRS-11 score was -2.5 (SD 4.5) after initial tanezumab and 0 (SD 0) with continued treatment. For the delayed group, the mean change in NRS-11 score was -0.4 (SD 2.1) with placebo and -1.4 (SD 1.9) after tanezumab. For the early group, the mean change in PROMIS-PI T-score was -6.2 (SD 10.9) after initial tanezumab and -0.4 (SD 2.0) with continued treatment. For the delayed group, the mean change in PROMIS-PI T-score was 1.1 (SD 2.9) after placebo and -3.3 (SD 4.1) after tanezumab. Discussion: For SWN patients with moderate-to-severe pain, addition of tanezumab was associated with decreases in pain intensity and pain interference. Although these changes reflect clinically meaningful differences per published literature, they were not statistically significant. This study was underpowered due to poor accrual and a larger study in this patient population is warranted.
CTNI-50. UPDATE REPORT OF THE RESPECT-GBM PHASE I/IIA DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA [RGBM] VIA CONVECTION ENHANCED DELIVERY (CED)
Authors: Andrew Brenner, Joel Michalek, Melissa Moore, Marc Hedrick, Ande Bao, William Phillips, Toral Patel, Jeffrey Weinberg, John Floyd, Michael Youssef, Shiliang Huang, Norman LaFrance
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A Phase1/2a dose-escalation trial was initiated to determine the safety and recommended phase2 186RNL-dose(RP2D). Liposomal-rhenium-186(186RNL) is a source of high-energy beta-particles with gamma-photons representing attractive brain CED properties. METHODS A 3 + 3 Phase1 design was implemented per protocol [modified-Fibonacci dosing sequence]. We report safety and overall survival (OS) in 27 patients assigned to cohorts1-8. Patients with biopsy proven recurrent glioma had computerized treatment planning and placement of up to 5 intracranial catheter(s) single CED-186RNL administration. Whole body planar and SPECT/CT imaging through ~1 week following treatment was performed. Patients were followed for safety, sufficiency of delivery and OS. The significance of variation in OS was assessed with a 2-sided logrank test with α = 0.05. RESULTS Cohorts dosing ranged from 1mCi-in-0.6mL to 41.5mCi-in-16.3ml, MTD not reached, and no CED failures. No dose limiting toxicities were observed. Most common AEs were pre-existing GBM related signs/symptoms [weakness, fatigue, headache, seizure, scalp discomfort after CED] and &amp;gt;80% of AEs unrelated/unlikely relationship. Median absorbed radiation dose to the tumor (MARDT) was 308.4 Gy (8.9 Gy to 739.5 Gy). Patients were stratified by MARDT (&amp;lt; 100 Gy, ≥100 Gy). In all patients (N = 27), the median overall survival (OS) was 8 months (m), 95% CI 5 m to 13 m). In those receiving &amp;lt;100 Gy (N = 10), the median OS was 5 m (95% CI 1 m to 11 m) and in those with ≥ 100 Gy (N = 17) the median was 12 m (95% CI 5 m to 30 m), p &amp;lt; 0.001. CONCLUSION A single administration of 186RNL by CED in recurrent glioma patients is feasible, safe, and potentially effective in increasing overall survival when &amp;gt;100Gy radiation is delivered to the tumor. A RP2D of 22.3mCi in 8.8mL was selected for patients with tumor size of ≤20mL in the planned Phase 2B.